[Oncologic follow-up in head and neck cancer patients]. / Onkologische Nachsorge von Kopf-Hals-Tumor-Patienten.

Despite medical treatment according to evidence-based guidelines, approximately 25-30% of all head and neck tumor patients suffer a disease relapse, depending on tumor stage and entity. The primary goal of systematic follow-up examinations is early detection and treatment of recurrent tumors or metachronous secondary tumors, but it also serves to rule out distant metastasis. Secondary goals are the diagnosis and management of treatment-associated side effects to optimize quality of life. Because of an especially high relapse risk in the first 2 years after treatment, close-knit clinical controls are recommended, e.g., quarterly. Later on, the clinical control interval can be extended to 6 months. Cross-sectional diagnostic imaging of the primary tumor region is performed annually and when screening for possible distant metastases, or upon clinical suspicion of recurrence. After 5 years without tumor recurrence, the structured clinical follow-up is usually completed.

Changes in circulating exosome molecular profiles following surgery/(chemo)radiotherapy: early detection of response in head and neck cancer patients.

BACKGROUND: Head and neck cancers (HNSCC) are highly immunosuppressive. Plasma-derived exosomes of HNSCC patients carry immunomodulatory molecules, and their cargo correlates with clinical parameters. Here, we evaluated the exosomal molecular profile for early detection of treatment failure in locally advanced HNSCC patients treated with conventional therapy. METHODS: Plasma from 17 HNSCC patients was collected before, during, and after treatment by surgery with adjuvant (chemo)radiation and at recurrence. Exosomes were isolated by size-exclusion chromatography. Total exosomal protein (TEP) was used to estimate exosome load and on-bead flow cytometry to evaluate relative fluorescence intensity (RFI) of tumour-associated and immunoregulatory proteins on exosomes. Exosomal effects on the activity of and adenosine production by T cells was assessed by flow cytometry and mass spectrometry. RESULTS: TEP and the ratio of tumour-/immune-cell-derived exosomes varied during and after therapy with an overall decrease in the tumour-free follow-up but an increase at recurrence. RFI values of immunoregulatory proteins on exosomes, their ability for T cell inhibition and adenosine production changed during and after therapy. PD-L1 was the earliest discriminator for treatment failure and disease-free survival. CONCLUSIONS: Monitoring of plasma exosomes during therapy represents a promising opportunity for early detection of treatment failure and risk stratification to delay/avoid recurrence.

Influence of travel burden on tumor classification and survival of head and neck cancer patients.

PURPOSE: Cancer patients have to overcome various barriers to obtain diagnostics and treatment at head and neck cancer centers. Travel distance to a specialized hospital may result in psychosocial and financial distress, thus interfering with diagnostics, treatment, and follow-up care. In this study, we have aimed to analyze the association of travel distance with cTNM status, UICC stage at primary diagnosis, and survival outcomes of head and neck cancer (HNC) patients. METHODS: We have analyzed data of 1921 consecutive HNC patients diagnosed between 2014 and 2019 at the head and neck cancer center of the Comprehensive Cancer Center Ulm (CCCU), Germany. Postal code-based travel distance calculation in kilometers, TNM status, and UICC stage were recorded at initial diagnosis. The assembly of travel distance-related groups (short, intermediate, long-distance) has been investigated. Moreover, group-related survival and recurrence analysis have been performed. RESULTS: In contrast to observations from overseas, no association of travel distance and higher cTNM status or UICC stage at primary diagnosis has been observed. Furthermore, no significant differences for recurrence-free survival and overall survival by travel distance were detected. CONCLUSION: In southern Germany, travel distance to head and neck cancer centers seems to be tolerable. Travel burden is not synonymous with travel distance alone but also involves sociodemographic, monetary, and disease-specific aspects as well as accessibility to proper infrastructure of transport and health care system.

Evaluation of a curved surgical prototype in a human larynx.

PURPOSE: It is not always possible to create linear access to the larynx using a rigid operating laryngoscope for microlaryngoscopy. In this study, we evaluate the usability of a novel curved surgical prototype with flexible instruments for the larynx (sMAC) in a simulation dummy and human body donor. METHODS: In a user study (n = 6), head and neck surgeons as well as medical students tested the system for visualization quality and accessibility of laryngeal landmarks on an intubation dummy and human cadaver. A biopsy of the epiglottis was taken from the body donor. Photographic and time documentation was carried out. RESULTS: The sMAC system demonstrated general feasibility for laryngeal surgery. Unlike conventional microlaryngoscopy, all landmarks could be visualized and manipulated in both setups. Biopsy removal was possible. Visibility of the surgical field remained largely unobstructed even with an endotracheal tube in place. Overall handling of the sMAC prototype was satisfactorily feasible at all times. CONCLUSION: The sMAC system could offer an alternative for patients, where microlaryngoscopy is not applicable. A clinical trial has to clarify if the system benefits in clinical routine.

[Robotics in otorhinolaryngology, head and neck surgery]. / Roboterassistierte Chirurgie in der Hals­Nasen-Ohren-Heilkunde.

In many surgical specialities, e.g., visceral surgery or urology, the use of robotic assistance is widely regarded as standard for many interventions. By contrast, in European otorhinolaryngology, robotic-assisted surgery (RAS) is rarely conducted. This is because currently available robotic systems are not adequately adapted to the restricted space and partially difficult access to surgical fields in the head and neck area. Furthermore, RAS is associated with high costs at present. In some Anglo-American regions, robot-assisted surgery is already used regularly for different indications, particularly in transoral surgery of oropharyngeal tumors. Several feasibility studies demonstrate multiple fields of application for RAS in head and neck surgery. For standard use, the robotic systems and surgical instruments need to be reduced in size and adapted to application in the head and neck area.

[Robot-assisted head and neck surgery]. / Robotik in der Kopf-Hals-Chirurgie.

Robot-assisted surgery (RAS) has already been approved for several clinical applications in head and neck surgery. In some Anglo-American regions, RAS is currently the common standard for treatment of oropharyngeal diseases. Systematic randomized studies comparing established surgical procedures with RAS in a large number of patients are unavailable so far. Experimental publications rather describe how to reach poorly accessible anatomical regions using RAS, or represent feasibility studies on the use of transoral robotic surgery (TORS) in established surgical operations. With general application of RAS in clinical practice, the question of financial reimbursement arises. Furthermore, the technical applications currently on the market still require some specific improvements for routine use in head and neck surgery.

[Effects of the SARS-CoV­2 pandemic on the otolaryngology university hospitals in the field of research, student teaching and specialist training]. / Auswirkungen der SARS-CoV­2-Pandemie auf die universitäre Hals-Nasen-Ohren-Heilkunde im Bereich der Forschung, Lehre und Weiterbildung.

BACKGROUND: From spring 2020, SARS-CoV­2 began to spread worldwide, with what is now known as the first wave of the pandemic, starting in March 2020. This resulted in restructuring and shift of resources at many hospitals. The aim of our work was to detect the effects of the pandemic on the german Oto-Rhino-Laryngology (ORL) university hospitals in terms of research, student teaching and further specialist training. MATERIAL AND METHODS: The chairmen of the 39 ORL university hospitals in Germany were asked about the effects of the pandemic on research, student teaching and ORL specialist training (residency) in the period from March to April 2020 using a structured online survey. RESULTS: All 39 chairmen took part in the survey. Of these, 74.4% (29/39) stated that their research activities had deteriorated as a result of the pandemic. In 61.5% (24/39) pandemic-related research issues were addressed. All hospitals reported a restriction for in-house teaching and 97.5% (38/39) introduced new digital teaching methods. During the observation period, 74.4% of the chairmen did not see ORL specialist training (residency)at risk. CONCLUSION: Our results provide an insight into the heterogeneous effects of the pandemic. The fast processing of pandemic-related research topics and the introduction of innovative digital concepts for student teaching impressively demonstrates the great innovative potential and the ability of the ORL university hospitals to react quickly in order to maintain their tasks in research, student teaching and ORL specialist training in the best possible way even during the pandemic.

Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma.

INTRODUCTION: The number of aging cancer patients has increased continuously and will do so further in the future. The immune system of elderly people experiences critical changes over the time. Therefore, tumor-induced changes in the immune system are believed to differ in young and elderly cancer patients as well. METHODS: The effect of aging on the immune system was measured in peripheral blood lymphocytes (PBL) of healthy volunteers (n = 48, 21-84 yrs.) divided into three different age groups. Seventy years was set as a cut-off for defining subjects as elderly. Results were compared to two groups of adult cancer patients, which donated PBL and tumor infiltrating lymphocytes (TIL): young cancer patients (40-69 yrs.; blood: n = 13; TIL: n = 17) and elderly cancer patients (70-90 yrs.; blood: n = 20; TIL: n = 15) with head and neck squamous cell carcinoma (HNSCC). Frequencies and phenotypes of CD4+ and CD8+ T cells as well as regulatory T cells (Treg) were assessed by flow cytometry. RESULTS: We observed lower frequencies of CD8+ cytotoxic T cells during aging in both groups. Frequencies of tumor infiltrating regulatory T cells were significantly higher than in the peripheral blood but showed a significant decline in older tumor patients. With increasing age, expression of immunosuppressive CD73 and CCR7 was lower and expression of PD1 elevated on peripheral T cells in healthy volunteers and tumor patients. CONCLUSION: Immunosenescence takes place in healthy donors and cancer patients. Our results suggest that in elderly tumor patients, the immune system is impaired and the tumor-induced immune escape is less pronounced. The increased expression of PD1 implies the potential for effective immunotherapies in elderly, as treatment with checkpoint inhibitors could be more beneficial for elderly HNSCC patients.

[Oncoimmunology in old age]. / Onkoimmunologie im Alter.

Physiological aging processes of the immune system are associated with an increased susceptibility to infectious, autoimmune and tumor diseases. In accordance with the general demographic development the number of tumor patients in advanced age also increases. An end to this development is not yet foreseeable. In tumor treatment, immunotherapy with checkpoint inhibitors is becoming increasingly more important; however, only a few studies on the efficacy and side-effect profiles in older patients exist so far. In this review article the changes in the immune system in old age and the influence on carcinogenesis are discussed. In addition, the current state of research on the immunotherapy of patients in advanced age who suffer from head and neck cancer is presented.

Adenosine production in mesenchymal stromal cells in relation to their developmental status.

BACKGROUND: Mesenchymal stromal cells (MSC) are multipotent progenitor cells found in the tumor microenvironment. They have an innate and regulatory immune activity, and they are able to produce immunosuppressive adenosine (ADO) via their ectonucleotidases CD39 and CD73. The present study explores ADO metabolism of MSC in relation to their developmental status. METHODS: We analyzed MSC (n = 6), chondrogenic progenitor cells (CPC, n = 8), and chondrocytes (n = 8) for surface markers by flow cytometry. The ability to hydrolyze ATP and to produce ADO was tested by luminescence assays and mass spectrometry. RESULTS: Significant differences in the surface marker expression of MSC, CPC, and chondrocytes were seen. While the expression of CD73 was observed to be the same on all cell types, the expression of the ectonucleotidase CD39 was significantly increased on MSC. Consequently, production of ADO was most abundant in MSC as compared with chondrocytes and CPC. CONCLUSION: Mesenchymal stromal cells are potent producers of ADO and are, therefore, able to increase immunosuppression. As MSC differentiate into chondrocytes, they lose this ability and may take on other functions.

Treatment-induced changes of lymphocyte subsets in patients with adenoid cystic carcinoma of the head and neck.

PURPOSE: Adenoid cystic carcinoma (ACC) of the head and neck is a rare and highly malignant tumor, characterized by perineural growth and early distant metastases. The composition of immune cells in the peripheral blood and the tumor microenvironment is critical to tumor growth and control. However, little is known about the frequency and function of the relevant immune cell subsets in this entity. METHODS: In ACC patients (n = 11) and matched healthy donors (n = 11), the frequency of peripheral blood T and B cells was measured by flow cytometry at different treatment stages of disease (24 samples). Cells were further characterized by their expression of CCR7, PD-1, CD39 and CD73. Tumor-infiltrating lymphocytes (TIL) were analyzed by immunohistochemistry for ten patients and for three patients by flow cytometry. RESULTS: CD4+ T cells had significantly lower frequency after radiotherapy (RT). All other cell frequencies, including Treg, were stable through course of the disease. In B cells, CD73 was reduced after RT. CCR7 expression on T and B cells in patients with relapse/metastases (R/M) differed significantly from patients with active disease. PD-1 remained stable. Treg were more present in TIL compared to peripheral blood. CONCLUSION: Composition of lymphocyte subgroups behaves similar to squamous cell carcinoma in the head and neck, except for Treg, which remained stable. Nevertheless, the CD4+/Treg ratio was lower after RT, which could stand for an immunosuppressive effect in these patients. Therefore, it could be beneficial treating ACC with combined RT and immunomodulatory drugs.

[Laryngectomy-still state of the art?] / Die Laryngektomie ­ noch zeitgemäß?

Total laryngectomy provides a curative approach for patients with advanced laryngeal and hypopharyngeal cancer without distant metastasis. Especially in stage cT4a disease, laryngectomy is superior to primary radio(chemo)therapy in retrospective studies. Further relevant indications for the procedure are tumor-related laryngeal dysfunction such as dysphagia and aspiration, as well as cancer recurrence after primary radio(chemo)therapy. The surgical procedure is highly standardized, with an appropriate safety profile. The subsequent loss of voice must be compensated by voice rehabilitation (voice prosthesis, ructus). The current overview provides information about indications for laryngectomy, preoperative clinical diagnostics, the surgical procedure, complications, alternative treatment, rehabilitation, and prognosis. Total laryngectomy remains a standard procedure in modern head and neck oncology.

[Salivary gland malignancies-highlights of the 2019 ASCO Annual Meeting]. / Maligne Speicheldrüsentumoren ­ Highlights der ASCO-Jahrestagung 2019.

BACKGROUND: Due to their comparatively low incidence, salivary gland carcinomas have only been the subject of isolated clinical studies in recent years. In addition, surgery with/without adjuvant radiotherapy is considered standard treatment. Systemic therapies have received little attention and are only used for advanced and distantly metastasized salivary gland malignancies. OBJECTIVE: The contributions with the highest relevance for this year's meeting of the American Society of Clinical Oncology (ASCO) were to be reviewed. MATERIALS AND METHODS: A total of 12 contributions pertaining to clinical studies on salivary gland malignancies were identified, eight of which were classified as relevant for future changes to the therapeutic landscape. RESULTS: Three studies dealt with different combinations of a checkpoint blockade, and each showed a low response rate. In addition, studies on targeted therapies depending on the results of a mutation analysis and expression of HER2 or the androgen receptor were presented. CONCLUSION: A favorable response of HER2-positive salivary gland carcinomas to an antibody-drug conjugate could be shown. Furthermore, no convincing data regarding response to programmed cell death protein 1 (PD1)/programmed death ligand 1 (PD-L1) inhibitors in advanced salivary gland cancer were presented. Further studies and ideas for new treatment approaches will be needed to improve the therapeutic options for patients with salivary gland carcinoma.

Polyfunctionality of CD4+ T lymphocytes is increased after chemoradiotherapy of head and neck squamous cell carcinoma.

BACKGROUND: For head and neck squamous cell cancer (HNSCC), standard therapy consists of surgery, radiation, and/or chemotherapy. Antineoplastic immunotherapy could be an option in an adjuvant setting and is already in palliation. A functional immune system is a prerequisite for successful immunotherapy. However, effects of the standard-of-care therapy on the patients' immune system are not fully understood. METHODS: Peripheral blood mononuclear cells (PBMC) were collected from patients with HNSCC (n = 37) and healthy controls (n = 10). PBMC were stimulated with staphylococcal enterotoxin B (SEB). Simultaneous expression of various cytokines was measured in CD4+ and CD8+ T cells by multicolor flow cytometry, and polyfunctional cytokine expression profiles were determined on a single-cell basis. RESULTS: Expression levels of all measured cytokines in CD4+ T cells were higher in patients after chemoradiotherapy (CRT) as compared to untreated HNSCC patients or normal controls. After CRT, the frequency of polyfunctional CD4+ T cells, which simultaneously expressed multiple cytokines, was significantly increased as compared to untreated patients (p < 0.01). CONCLUSION: CRT increases polyfunctionality of CD4+ T cells in HNSCC patients, suggesting that standard-of-care therapy can promote immune activity in immune cells. These polyfunctional CD4+ T cells in the blood of treated HNSCC patients are expected to be responsive to subsequent immunotherapeutic approaches.

[B cells in head and neck oncology]. / B-Zellen in der Kopf-Hals-Onkologie.

As immunotherapy is becoming increasingly important in the treatment of head and neck cancer, a fundamental understanding of the immunological relationships in the tumor microenvironment is required. The importance of tumor-infiltrating B cells (TIL-B) has been largely neglected so far. In the current literature, however, a significant influence of B cells on tumor growth is described, so that this cell population is now also perceived as a therapeutic target structure. Regulatory B cells (Breg) represent a subset of B cells with immunosuppressive properties. In addition to the secretion of IL-10, Breg can be defined by their ability to produce adenosine. Adenosine is known as an immunosuppressive messenger in the tumor microenvironment whose effect can be prevented by immunotherapeutic approaches. Understanding the tumor immunological relationships, including the different B­cell functions, can help to effectively combine standard approaches including surgery or radiochemotherapy with immunotherapy. In the present article, recent findings on B cells and adenosine in head and neck cancer are described.

[Immuno-, radio-, and chemotherapeutic studies in head and neck cancer : Highlights of the ASCO Annual Meeting 2017]. / Immun-, radio- und chemotherapeutische Studien bei Kopf-Hals-Tumoren : Highlights der ASCO-Jahrestagung 2017.

In recent years, immunotherapy has been shown to be a promising approach for the treatment of various tumor entities. Due to further pharmacological developments and new studies, the checkpoint inhibitors have now arrived in the clinic. To date, patients with cancers in the head and neck region have benefited from these agents as part of a palliative therapy. Current clinical trials are testing other indications for the checkpoint inhibitors as monotherapy or in combination with other therapeutic approaches. The following article summarizes the highlights of the American Society of Clinical Oncology (ASCO) Annual Meeting.

[Immunotherapy highlights of the ASCO annual meeting 2018 for head and neck cancers]. / Highlights der ASCO Jahrestagung 2018 zur Immuntherapie von Kopf-Hals-Tumoren.

BACKGROUND: Immunotherapeutic strategies are becoming increasingly more important for head and neck cancer and numerous clinical trials were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) 2018. OBJECTIVE: In this review the most interesting clinical trials and trial results for immunotherapy of head and neck cancer are summarized. MATERIAL AND METHODS: All abstracts and presentations on immunotherapy of head and neck cancer at the annual meeting of the ASCO 2018 were screened to select the most interesting trials for a more detailed analysis. RESULTS: For head and neck cancer, practice changing phase III trial results were missing, but several noteworthy new strategies and trial results for immunotherapy were presented. Neoadjuvant immunotherapy trials, results concerning immunotherapy in old age, prognostic implications of immune-mediated adverse events and new immunotherapy combinations are summarized in this article. CONCLUSION: The role of immunotherapy for the treatment of head and neck cancer is markedly increasing. Many pioneering trials are currently ongoing, in the phase of data analysis or in planning.

Application of a computer-assisted flexible endoscope system for transoral surgery of the hypopharynx and upper esophagus.

Zenker's diverticulum is a common pathology in the transition zone of the posterior hypopharynx and esophagus. Surgical treatment is routinely performed by ENT and general surgeons. Besides the traditional open transcervical diverticulectomy, the introduction of transoral rigid treatment led to a paradigm change and is now the preferred treatment option for patients who are fit for general anesthesia. The implementation of interventional flexible endoscopy has opened another new micro-invasive approach for patients with high morbidity. Here, we present the potential utilization of a flexible, single port, robot-assisted, and physician-controlled endoscope system to facilitate transoral surgical access to the hypopharynx and upper esophagus. Transoral surgery of the hypopharynx and upper esophagus was performed in human cadavers (n = 5) using the Flex System (Medrobotics, Raynham, USA). Anatomical landmarks were identified, and posterior cricothyroid myotomy was performed with compatible flexible instruments in all cases. The approach to the hypopharynx and upper esophagus using the Flex system is feasible in a cadaveric model. Myotomy with a flexible tool and needle knife (from the perspective of treatment of Zenker´s diverticulum) was successful in all cases. Visualization of the surgical site with the system's HD camera is suitable and the flexible instruments meet the special needs of a micro-invasive transoral approach. Zenker´s diverticulum can be potentially treated with a transoral minimally invasive approach using a computer-assisted flexible endoscope system. This setup could be of advantage in patients with reduced mobility of the cervical spine to prevent open transcervical surgery. In our study, the Flex system enabled advanced visualization of the surgical site and extended intervention options, compared to standard flexible endoscopic treatment. However, general anesthesia is mandatory for the presented approach. Application in live patients with actual pathologies of the hypopharynx and upper esophagus will have to prove suitability for the treatment of Zenker's diverticulum. Further development of the system could include improved instrumentation and an adoption by other disciplines with challenging anatomy such as colorectal surgery.

Response Evaluation in Head and Neck Oncology: Definition and Prediction.

Curative treatment of head and neck squamous cell carcinoma includes surgery and/or (chemo)radiation, whereas in the palliative setting, chemotherapy and/or immunotherapy represent(s) the standard approach. With regard to quality control, methods for determining treatment response are sorely needed. For surgical therapy, histopathology is the standard quality control. Established criteria for high-risk patients include resection margins of the primary tumor and extracapsular extension of lymph node metastases. After definitive chemoradiation, treatment response is generally evaluated by tomographic imaging combined with endoscopy including re-biopsy of the tumor region. Single-cycle induction chemotherapy may be used to determine the radiosensitivity of tumors, helping to define surgical and nonsurgical treatment options. Innovative approaches with implications for prognosis include the analysis of immune infiltrates, liquid biopsy, molecular characterization (proteomics, genomics), molecular and functional imaging (PET-CT, PET-MRI), as well as advanced imaging data analysis (radio[geno]mics/texture analysis). Human papilloma virus, as a prognostically relevant parameter, is currently being investigated for de-escalation strategies. With regard to the extended personalization of oncologic therapy, markers predicting treatment response are desirable and seem to be important, also from a socioeconomic perspective.